Process for the production of progesterone derivatives

ABSTRACT

A process for the production of progresterone derivatives of general formula I ##STR1## in which   symbolizes a single bond or a double bond, 
     X represents a hydrogen atom, a fluorine atom or a methyl group and 
     V means a methylene group, an ethylene group, an ethylidene group or a vinylidene group, is described.

The invention relates to a process for the production of progesteronederivatives of general formula I ##STR2## in which symbolizes a singlebond or a double bond,

X represents a hydrogen atom, a fluorine atom or a methyl group and

V means a methylene group, an ethylene group, an ethylidene group or avinylidene group, which is characterized in that a nitrile of thegeneral formula II ##STR3## in which X and V have the above-mentionedmeaning and in which Y and Z together are an alkylenedioxy group with 2to 6 carbon atoms and W represents a hydrogen atom or in which

Y symbolizes an alkyloxy group with up to 4 carbon atoms, a benzyl groupor an acyloxy group with 2 to 8 carbon atoms, and Z and W represent twohydrogen atoms or together mean a carbon-carbon bond,

with a Grignard reagent of the general formula III

    Ch.sub.3 --Mg--Z                                           (III),

in which Z symbolizes a chlorine atom or a bromine atom, is reacted andthe intermediate products formed are hydrolyzed by acids.

By an alkylenedioxy group Y and Z of the nitriles of the general formulaII is to be understood, for example, a 1,2-ethylenedioxy group, a1,3-propylenedioxy group, a 2,2-dimethyl-1,3-propylenedioxy group or a2,3-butylenedioxy group.

Suitable alkoxy groups Z are, for example, the methoxy group, the ethoxygroup, the isopropyloxy group or the tertbutyloxy group.

Suitable acyloxy groups are, among others, the acetoxy group, thepropionyloxy group, the dimethylacetoxy group, the trimethylacetoxygroup and the benzoyloxy group.

The Grignard reagent necessary for carrying out the process according tothe invention can be produced in the usual way, for example by methylchloride or methyl bromide in an either such as diethyl ether,diisopropyl ether, dibutyl ether, 1,2-dimethoxyethane or tetrahydrofuranbeing reacted with magnesium chips. Because of its relatively lowboiling point and its not too low flash point, tetrahydrofuran isespecially suitable. These Grignard reagents can be used directly forthe reaction with the nitriles of general formula II. But the ethersuitably is largely removed by distillation before the reaction andreplaced by toluene. (It is noted that in comparison with benzene,toluene has the advantage of substantially lower toxicity, and incomparison with xylenes, toluene has the advantage of a low boilingpoint). It not has only the advantage that a large part of the ether canbe recovered problem-free but also that the reaction can be performedunder mile conditions and the working up of the reaction mixture isgreatly facilitated.

To carry out the reaction, at least 4 moles of Grignard reagent isnecessary to reach high yields in the process product. The reaction isperformed at a temperature of -20° C. to +10° C.--preferably at -5° to+5° C. Under these conditions, the reaction time is about 30 to 180minutes.

After the reaction has been completed, the reaction mixture, as in thecase of Grignard reactions, is usually decomposed. This decompositioncan take place, for example, with an aqueous solution of tetrasodiumsalt of ethylenediaminetetraacetic acid; however, this reagent issomewhat expensive. The decomposition of the reaction mixture withaqueous ammonium chloride solution has been proven quite suitable andproblem-free.

After the decomposition has been completed, the toluene can be removedby steam distillation and an intermediate product is obtained whichconsists of a mixture of the progesterone derivative of the generalformula I and the imino compounds of formulas IV and V ##STR4## (inthese formulas, , X, Y, Z, W and V have the above-mentioned meaning).

This product can be hydrolyzed problem-free by acids to the progesteronederivatives of the general formula I.

This hydrolysis can be performed, for example, so that the intermediateproduct dissolves in a lower alcohol--such as methanol, ethanol orisopropanol, mixed with an acid, such as hydrochloric acid, sulfuricacid or p-toluenesulfonic acid and heated. After the reaction has beencompleted, the reaction product can, for example, be precipitated withwater, and suitably, care is taken that the acid is neutralized.

According to tests so far available, the yield of process product isabout 90% of theory. It can be possibly be further increased byoptimizing the process parameters.

It is very surprising for one skilled in the art that the progesteronederivatives of the general formula I can be produced by directGrignardation of the nitriles of the general formula II.

In 1959, P. de Ruggieri et al. had already produced17alpha-hydroxy-pregnan-20-one derivatives from cyanohydrins of17-oxosteroids. For this purpose, they had etherified the 17-hydroxygroup of the cyanohydrin by reaction with 2,3-dihydropyran and then theyreacted the 17-tetrahydropyranyl ether with a Grignard reagent offormula III. The direct Grignardation of unprotected cyanohydrins is notpossible in the opinion of the authors, since the Grignard reagent leadsto the dissociation of the cyanohydrin, and the initial ketone results,which forms the corresponding methyl carbinol with the Grignard reagent.(J. Amer. Chem. Soc., 81, 1959, p. 5725).

Also, L. F. Fieser et al. (L. F. Fieser and M. Fieser, "Steroids" VerlagChemie, Weinheim DE, 1961, p. 742) and E. Oliveto (J. Fried and J. E.Edwards (Ed) "Organic Reactions in Steroid Chemistry" Vol. II; VanNostrand Reinhold Comp. New York et at. 1972, p. 132) have held the viewthat the direct Grignardation of unprotected cyanohydrins is notpossible

When syntheses of this type were performed, cyanohydrins were alwaysused even more recently as initial substances, whose 17-hydroxy groupwas protected. See, for example,

K. Annen et at. DE-A 34 27 486

I. Nitta et al. Bull Chem. Soc., Jpn. 58, 1985, 978

V. H. van Rhennen U.S. Pat. No. 4,500,461

J. V. M. Batist et al. EP-A 0263569 and

A. E. V. Popova et al., ref. C. A. 102, 1985, 167.005e

The advantages of the process according to the invention lie not only inthat a reaction step is saved, they also lie in the very simplefeasibility of the process according to the invention and the highyields of process products.

The following embodiment is used to explain in more detail the processaccording to the invention:

EXAMPLE

100 1 of tetrahydrofuran is distilled off from 219 1 of a 3 molarsolution of methylmagnesium chloride in tetrahydrofuran under nitrogenat standard pressure. Then, 725 1 of toluene is added to the mixture sothat the temperature does not fall below 80° C. and 300 1 of thetetrahydrofuran-toluene mixture is distilled off.

The solution is allowed to cool to 0° C., it is mixed with stirringwithin 30 minutes with a suspension of 50 kg of3,3-ethylenedioxy-17beta-5-androsten-17alpha-ol in 150 1 of toluene, andthe temperature is not to exceed 5° C., and it is stirred for anotherhour at 5° C.

Then, a solution of 25 kg of ammonium chloride in 200 1 of water isadded to the reaction mixture so that the reaction temperature does notexceed 80° C., it is acidified with hydrochloride acid up to a pH of6.5, heated for 20 minutes with stirring to 80° C., the organic phase isseparated, the aqueous phase is washed with 200 1 of toluene, theorganic phases are combined, they are mixed with 200 1 of water and thetoluene is distilled off by steam distillation.

After the cooling of the reaction mixture, the precipitated intermediateproduct is filtered off, washed with water, introduced in 500 1 ofmethanol, mixed with 6.5 1 of concentrated hydrochloric acid andrefluxed for 15 minutes. Then, the mixture is allowed to cool, it is putinto a solution of 12.5 kg of sodium acetate in 25 1 of water, 400 1 ofmethanol is distilled off and the residue is slowly mixed with 500 1 ofwater.

The precipitated product is filtered off, washed with water and dried at50° C. in a circulating drying oven.

48 kg of 17alpha-hydroxy-4-pregnene-3,20-dione with the melting point of210°-213° C. is thus obtained. (Purity of 93% according to HPCL.)

We claim:
 1. Process for the production of progesterone derivatives ofgeneral formula I ##STR5## in which symbolizes a single bond or a doublebond,X represents a hydrogen atom, a fluorine atom or a methyl group andV means a methylene group, an ethylene group, an ethylidene group or avinylidene group, which is characterized in that a nitrile of thegeneral formula II ##STR6## in which Y and Z together are analkylenedioxy group with 2 to 6 carbon atoms and , X and V have theabove-mentioned meaning and in which W represents a hydrogen atom or inwhich Y symbolizes an alkyloxy group with up to 4 carbon atoms, a benzylgroup or an acyloxy group with 2 to 8 carbon atoms, and Z and Wrepresent two hydrogen atoms or together mean a carbon-carbon bond, witha Grignard reagent of the general formula III

    CH.sub.3 --Mg--Z                                           (III),

in which Z symbolizes a chlorine atom or a bromine atom, is reacted andthe intermediate products formed are hydrolyzed by acids.
 2. Process forthe production of progesterone derivatives of general formula Iaccording to claim 1, wherein the reaction is performed with a solutionof a complex of the Grignard reagent with an ether in toluene. 3.Process for the production of progesterone derivatives of generalformula I according to claim 1, wherein the reaction is performed at atemperature of -20° C. to +10° C.
 4. Process for the production ofprogesterone derivatives of general formula I according to claim 2,wherein the reaction is performed at a temperature of -20° C. to +10° C.